The vinca alkaloids, a group of dimeric indole dihydroindoles, have achieved considerable prominence as marketed or experimental chemotherapeutic agents for the treatment of susceptible carcinomas, sarcomas, and leukemias. These agents are used both alone and in combination with other chemotherapeutic agents. As a class, the vinca alkaloids include compounds obtainable from the leaves of Vinca rosea, derivatives produced by chemical modification thereof and more recently, dimeric alkaloids produced by coupling two "monomeric" indoles via a modified Polonovski reaction--see Langlois and Potier, Tetrahedron Letters, 1099 (1076), Potier, et al., J.C.S. Chem. Comm., 670 (1975), Kutney et al., Heterocycles, 3, 205 (1975) and Atta-ur-Rahman Tetrahedron Letters, 2351 (1976).
A majority of the vinca alkaloids can be described by the following formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 and R.sup.5 are H and R.sup.4 is ethyl, deoxy VLB "A" is represented; where R.sup.1, R.sup.2 and R.sup.5 are the same as in deoxy VLB "A" but R.sup.3 is ethyl and R.sup.4 is hydrogen, deoxy VLB "B" is represented; and where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine is represented.
The above-mentioned alkaloids are described in the following publications: leurosine (vinleurosine--U.S. Pat. No. 3,370,057), VLB (vincaleukoblastine, vinblastine--U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and vincristine (leurocristine or VCR) (both in U.s. Pat. No. 3,205,220), and deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1958). Other alkaloids obtained from vinca rosea include 4-desacetoxy vinblastine (U.S. Pat. No. 3,954,773); 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (2'-hydroxy VLB--U.S. Pat. No. 3,890,325) and vincadioline (3'-hydroxy VLB--U.S. Pat. No. 3,887,565).
Two of the above alkaloids, VLB and vincristine, are now marketed as drugs for the treatment of malignancies, particularly the leukemias and related diseases in humans. Of these marketed compounds, vincristine is a most active and useful agent in the treatment of leukemias but is also the least abundant of the antineoplastic alkaloids of Vinca rosea. Jovanovics et al.--U.S. Pat. No. 3,899,493--have developed an elegant oxidative procedure for converting the more abundant alkaloid VLB to vincristine employing chromic acid in acetone and acetic acid at about -60.degree. C. The same procedure has been used to prepare leuroformine (N-formylleurosine) from leurosine--see Belgian Pat. No. 811,110. Leuroformine has also been found in extracts of leaves of Vinca rosea. This alkaloid is currently undergoing a clinical trail in Europe chiefly in treatment of the leukemias and of multiple myeloma.
Chemical modification of VLB and vincristine has centered around hydrolysis of the 4-acetoxy group to yield 4-desacetyl VLB (DAVLB) or 4-desacetylvincristine (DAVCR) followed by reesterification with other acyl and amino-acyl groups--see U.S. Pat. Nos. 3,392,173 and 3,387,001--, and replacement of the C-3 ester function by an amide function--see Belgian Pat. No. 837,390. One of the former 4-acyl derivatives, the 4-N,N-dimethylglycine ester underwent a brief clinical trial and one of the latter, vindesine, (4-desacetyl VLB C-3 carboxamide) is currently being tested clinically against a variety of neoplasms.
Other chemical modification of the VLB molecule such as hydrolysis and decarboxylation of the C-18' carbomethoxy group has resulted in a loss of anti-cancer activity as has the formation of N-oxides; i.e., pleurosine (leurosine N-oxide). Oxidative attack on VLB under temperatures higher than -60.degree. C. has resulted in the formation of a chemotherapeutically inactive compound, vinamidine, represented by the following formula: ##STR2##
Vinamidine has been encountered in alkaloidal fractions from Vinca rosea leaves--see Tafur et al. J. Pharm. Sci., 64, 1953 (1975)--but the structure assigned therein (II on page 1956) is now believed to be incorrect and the above structure more closely represents the NMR, IR, and molecular spectral data obtained from physiochemical studies of the compound. Vinamidine may arise from oxidative attack on VLB in which a vicinal dihydroxy derivative is formed which, upon further oxidation, splits between the hydroxyl(4',5'bond) to yield a ring-opened derivative such as II above.
Kutney, et al, in Heterocycles 4, 1377 (1976), report the preparation of a leurosine lactam called by the authors 19'-oxoleurosine, formed by the action of iodine on leurosine and also refer to the preparation of 5'-oxoleurosine by the oxygenation of 3',4'-dehydrovinblastine or of leurosine.
It is an object of this invention to prepare stable 5'-oxygenated derivatives of leurosine and leuroformine as well as other novel 5'-derivatives thereof.